Category:Lipid-lowering agents

A lipid-lowering agent is a medicine that lowers the concentration of one or more circulating lipoproteins in the blood, with the goal of reducing the patient's risk of atherosclerotic cardiovascular disease. The class is unified less by mechanism than by indication: the medicines in it act on cholesterol synthesis, on cholesterol absorption, on lipoprotein receptor cycling, on apolipoprotein metabolism, and on the triglyceride content of very-low-density lipoprotein, by distinct routes that converge on a common circulating endpoint.

The idea that the cholesterol of the blood had something to do with atheroma in the artery wall is older than any treatment of it. In 1913 the St Petersburg pathologist Nikolai Anitschkow reported that feeding cholesterol in sunflower oil to rabbits produced lesions in the aorta that looked, under the microscope, like the human atheromatous plaque.^[1] The clinical correlation took longer. In 1939 the Norwegian physician Carl Müller described a series of kindreds in which a hereditary tendency to extremely high blood cholesterol ran together with premature myocardial infarction.^[2] In the late 1940s Ancel Keys at Minnesota began collecting the international comparative data that would become the Seven Countries Study, and by the mid-1950s the Framingham Heart Study was producing prospective evidence that the serum cholesterol of an individual American predicted his future cardiovascular events. The diet-heart hypothesis was, by 1960, a working framework for prevention; what was missing was an effective medicine.

The first generation of lipid-lowering medicines arrived in the 1950s and 1960s without changing prognosis. Nicotinic acid in gram doses was reported by Altschul, Hoffer, and Stephen in 1955 to lower serum cholesterol, although the mechanism (suppression of hepatic VLDL secretion) was understood only later.^[3] Cholestyramine, a non-absorbable anion-exchange resin, was introduced in 1959 to bind bile acids in the intestinal lumen and force the liver to consume cholesterol to replace them. Clofibrate, the first fibrate, was developed at ICI and introduced in 1962 with broad enthusiasm; the WHO Cooperative Trial reported in 1978 that clofibrate did reduce non-fatal myocardial infarction but appeared to increase all-cause mortality, and the field of lipid lowering entered a decade of caution.^[4]

The discovery that changed the field was made in Tokyo. The Japanese microbiologist Akira Endo, working at the Sankyo company on the assumption that some fungus must produce a competitive inhibitor of the cholesterol-synthesis enzyme HMG-CoA reductase as a defense against cholesterol-utilising microbes, screened more than six thousand fungal broths between 1971 and 1976 and found one. The compound, isolated from Penicillium citrinum and named compactin (mevastatin), was the first statin.^[5] Sankyo abandoned mevastatin's clinical development for reasons that have never been fully explained. Two years later a separate fermentation programme at Merck, led by Alfred Alberts and the future Merck president P. Roy Vagelos, isolated a closely related compound from Aspergillus terreus; this was lovastatin, approved by the U.S. Food and Drug Administration in 1987 and the first statin to enter clinical use.^[6]

The mechanism by which a reduction in hepatic cholesterol synthesis lowered the LDL cholesterol of the blood had been worked out, in parallel, by Joseph Goldstein and Michael Brown at the University of Texas Southwestern in Dallas. Their study of fibroblast cell lines from children with homozygous familial hypercholesterolemia showed that the cells lacked a cell-surface receptor for LDL; without it, the liver could not clear circulating LDL particles, which accumulated and were deposited in arterial walls.^[7] Lowering intracellular cholesterol with a statin upregulated the LDL receptor by sterol-regulated transcription, and the receptor cleared the blood. Goldstein and Brown shared the 1985 Nobel Prize. The Scandinavian Simvastatin Survival Study (4S) in 1994 was the first large trial to test the cardiovascular outcome of statin therapy; it found a thirty-percent reduction in mortality in patients with established coronary disease and converted the cardiology community, almost overnight, into prescribers of statins.^[8] Simvastatin, pravastatin, atorvastatin (synthesised at Parke-Davis by Bruce Roth and approved in 1996), and rosuvastatin (AstraZeneca, 2003) followed.

The lipid-lowering pharmacopoeia continued to expand. The cholesterol absorption inhibitor ezetimibe, introduced by Schering-Plough in 2002, blocks intestinal sterol uptake at the NPC1L1 transporter and lowers LDL by a further 15-to-20 percent on top of a statin. The discovery in 2003 by the French geneticist Marianne Abifadel that a third gene, PCSK9, mutated in autosomal dominant familial hypercholesterolemia,^[9] together with the population-genetic observation by Helen Hobbs and Jonathan Cohen that humans with loss-of-function PCSK9 variants had lifelong low LDL and reduced cardiovascular events,^[10] opened a new pharmacological route. The PCSK9 inhibitors evolocumab (Amgen) and alirocumab (Sanofi/Regeneron), both fully human monoclonal antibodies, were approved in 2015 and demonstrated additional cardiovascular benefit on top of statin therapy in the FOURIER and ODYSSEY OUTCOMES trials. The omega-3 derivative icosapent ethyl, a purified eicosapentaenoic-acid ester, lowered cardiovascular events in the REDUCE-IT trial of patients with persistent hypertriglyceridaemia on statin therapy and was approved for that indication in 2019.^[11]

What began with rabbits fed cholesterol in Imperial Russia is, today, the largest single therapeutic-class expenditure in cardiovascular medicine. The statins alone account for more annual prescriptions in the United States than any other class of medicine. The current question, as it was for the hypertension trials forty years earlier, is no longer whether to treat but how aggressively, and in whom: the targets of LDL cholesterol, the criteria for adding a non-statin agent, and the role of newer routes (the small interfering RNA agent inclisiran, approved in 2021; the oral PCSK9 inhibitors and the ANGPTL3 inhibitors in late-stage trials) are the subject of guidelines that revise themselves on the schedule of large outcome trials.

By mechanism:

• Statins (HMG-CoA reductase inhibitors): atorvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin
• Fibrates (PPAR-alpha agonists, primarily triglyceride-lowering): fenofibrate
• PCSK9 inhibitors (monoclonal antibodies and siRNA): evolocumab
• Cholesterol absorption inhibitors (NPC1L1 antagonists): ezetimibe
• Omega-3 fatty acids: icosapent ethyl
• Nicotinic acid (niacin) in pharmacological doses: niacin

The bile acid sequestrants (cholestyramine, colestipol, colesevelam) and the more recent bempedoic acid and inclisiran belong in this category but did not appear in the 2026 initial-build batch and will be added as their individual pages are written.

The boundary of this category is "medicine prescribed primarily to reduce circulating lipoproteins for cardiovascular-event prevention." The omega-3 fatty acids appear here when used as a prescription medicine for hypertriglyceridemia, not when sold as a dietary supplement. The plant sterols and stanols used in functional foods are not included. The pharmacological actions on cholesterol of agents whose principal indication is something else (the antihypertensive probucol, the older antifungal griseofulvin) are noted on the respective medicine pages but those agents are not collected here. Hereditary disorders of lipoprotein metabolism are described, briefly, on the medicine pages where their treatment is the principal indication; a dedicated reference page on the dyslipidaemias themselves is planned but not yet built.

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.